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All-trans retinoic acid in acute promyelocytic leukaemia
Best Practice & Research Clinical Haematology Vol. 16, No. 3, pp. 419 –432, 2003 doi:10.1053/ybeha.2003.268, www.elsevier.com/locate/jnlabr/ybeha
6 All-trans retinoic acid in acute promyelocytic leukaemia Giuseppe Avvisati*
MD, PhD
Hematology, University Campus Bio-Medico, Via Emilio Longoni 83, Roma 00159, Italy
Martin S. Tallman
MD
Hematology– Oncology, Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago,USA
The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed. Key words: all-trans retinoic acid; acute promyelocytic leukaemia.
All-trans retinoic acid (ATRA) belongs to a class of chemical compounds structurally related to vitamin A and is one of the class of compounds known as retinoids. Some of these compounds, including vitamin A, have shown limited success in the prevention of cancer and anti-cancer therapy. The mechanism of action of retinoids in chemoprevention and therapy of cancers involves modulation of cell proliferation and differentiation. In fact, retinoids are capable of both inhibiting cell proliferation and inducing cell differentiation. These activities have been demonstrated particularly in haematopoietic and epithelial transformed cell lines.1 A direct consequence of these experimental data has been the use of ATRA in the induction treatment of acute promyelocytic leukaemia (APL). The incorporation of ATRA into the therapy of APL was the most significant step forward in the 25 years of treatment and prognosis of acute myeloid leukaemias; it produced dramatic therapeutic effects on APL, leading to very high rates of complete remission (CR) and cure. * Corresponding author. Tel.: þ39-06-2254-1749; Fax: þ39-06-2254-1456. E-mail address: [email protected] 1521-6926/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
420 G. Avvisati and M. S. Tallman
EARLY PHASE II STUDIES OF ATRA IN APL The use of ATRA in APL as a single therapeutic agent was pioneered in the late 1980s by investigators in China. Twenty-four APL patients were treated with 45 to 100 mg/m2/day of ATRA. Of these, eight patients had been either non-responsive or resistant to previous chemotherapy and the remaining 16 patients were previously untreated. All except one of the patients achieved complete remission with ATRA alone, without developing bone marrow hypoplasia. The study of bone marrow suspension cultures in 15/24 patients revealed that 14 of these patients had morphological maturation in response to the retinoic acid. The only patient not responding to retinoic acid in vitro was resistant to treatment with retinoic acid but achieved complete remission after addition of low-dose cytosine arabinoside (Ara-C). During the course of therapy, none of the patients showed any progresses in abnormal coagulation parameters. The only side-effects observed were mild dryness of the lips and skin, with occasional headaches and digestive symptoms. However, despite the high remission rate, eight patients relapsed after only 2 –5 months of complete remission.2 The second report on the use of ATRA in APL was that of the French investigators who treated 22 APL patients with 45 mg/m2/day for a total of 90 days. Although only 4/22 were newly diagnosed, 14 achieved complete remission without bone marrow (BM) hypoplasia through a differentiation effect of treatment, as suggested by the presence of Auer rods in the maturing cells. Moreover, at remission, the t(15;17) initially present in 20 patients was not found. Skin and mucosal dryness, hypertriglyceridaemia, and an increase in hepatic transaminase were frequently observed. Eleven patients had bone pain while four patients had hyperleukocytosis. Maintenance treatment with low-dose chemotherapy or ATRA did not prevent early relapses.3 Following these results, a tremendous interest in the clinical use of ATRA in APL was generated. As a consequence, since then, several groups have begun to utilize this therapeutic agent in relapsed as well as newly diagnosed APL patients. A summary of these early phase II studies is reported in Table 1. In particular, the study of Warrell et al indicated, for the first time, that clinical response to ATRA in APL was linked to the expression of an aberrant RARa (retinoic acid receptor-a) nuclear receptor and that its molecular detection could be a useful marker for detecting residual leukaemia in APL patients.4 In the study of Chen et al, the very high rate of complete remission (CR)—94%— was followed by a relapse rate of about 40%. However, patients who relapsed after
Table 1. ATRA alone as induction treatment in APL patients (early phase II studies). Reference
Year
ATRA mg/m2
2 3 4 5 6 7 8
1988 1990 1991 1991 1992 1992 1994
45–100 45 45 60–80 45 50 45
Number of patients
CR(%)
24 22 11 50 11 7 51
96 64 82 94 64 71 86
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a chemotherapy-maintained CR could be effectively re-induced into second CR by ATRA. However, if relapse occurred after a CR maintained by both ATRA and chemotherapy, the sensitivity of newly emerged leukaemic clones to ATRA was greatly reduced. As a consequence, these investigators suggested that ATRA should be replaced by conventional chemotherapy as soon as CR is achieved.5 Finally, the study of Frankel et al concluded that ATRA was an effective agent in inducing remission in patients with a molecular diagnosis of APL, but that remissions were short and resistance developed rapidly. However, ATRA followed by consolidation chemotherapy was associated with longer survival times when compared with historical controls treated only with chemotherapy.8 From these early phase II studies, in which ATRA had been utilized as single induction agent, it was evident that, compared with standard chemotherapy, ATRA acted as a specific differentiative agent on leukaemic promyelocytes, inducing higher rates of CR, ranging from 64 to 100%, without causing bone marrow hypoplasia or exacerbation of the coagulopathy. Moreover, the toxicity was very different from that caused by standard chemotherapy. The toxicity ranged from occasionally severe hyperleukocytosis to skin and mucosa dryness, hypertriglyceridaemia, and an increase in hepatic transaminases. In some cases hyperleukocytosis was associated with severe bone pain, weight gain, dyspnoea, headache and fever.
THE DEFINITION OF RETINOIC ACID SYNDROME AND OF PSEUDOTUMOUR CEREBRI The most serious adverse effect during the induction treatment with ATRA was the appearance of a syndrome primarily characterized by fever and respiratory distress. Additional signs and symptoms included weight gain, lower extremity oedema, pleural or pericardial effusions, and episodic hypotension. This syndrome was named retinoic acid syndrome (RAS) by Frankel et al.9 These investigators had reported a total of nine of 35 APL patients treated with ATRA in whom this symptom complex occurred from 2 to 21 days after starting treatment. Post-mortem examinations in two of the three patients who died showed pulmonary interstitial infiltration with maturing myeloid cells. In 6/9 cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes. Leukapheresis, temporary cessation of therapy with ATRA, and cytotoxic chemotherapy in moderate doses were not useful once respiratory distress was established. However, the administration of high-dose corticosteroid (dexamethasone) therapy early in the course of the syndrome in four of these patients resulted in prompt symptomatic improvement and full recovery in three patients. Therefore, early recognition of the symptom complex of fever and dyspnoea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome. Since this initial description, however, no large series of RAS have been reported in detail until 1998 when Fenaux et al described 64 (15%) of the 413 patients included in the European APL group trial who experienced RAS during induction treatment.10 In this series, the main clinical signs were: respiratory distress (89%), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), hypotension (12%); 63 of the 64 patients had at least three of these signs, which developed after a median of 7 days. Thirteen patients required mechanical ventilation, and RAS was responsible for death in only five cases (1.2% of the total number of patients treated). Moreover, 86% of these
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64 patients achieved CR. Noteworthy, none of these patients who received ATRA for maintenance developed recurrent RAS. However, in this study, the occurrence of RAS was associated with lower event-free survival (EFS) and survival. The incidence, clinical course, and outcome of patients with newly diagnosed APL who developed RAS was also recently reported by the investigators participating in the North American Intergroup Protocol.11 Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome after a median time of 11 days of ATRA (range, 2 – 47). The median WBC count was 31 000/ml at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and was resumed in 19/36 patients (53%) with recurrence of RAS in three and one death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and eight achieved complete remission (CR). Among seven patients in whom ATRA was not re-started, and who were not treated with chemotherapy, five achieved CR and two died. In 8/44 patients in whom ATRA was not discontinued, subsequent resolution of the syndrome was observed in seven. Two deaths were definitely attributable to the syndrome, and no patient receiving ATRA as maintenance developed the syndrome. From these descriptions concerning the incidence and outcome of RAS in large cooperative trials it appears that, despite its incidence of 15 –25%, when recognized early and treated, the death rate is very low and none of the patients who experienced RAS had recurrence when ATRA was administered as maintenance. A recent analysis of the European APL 93 trial suggests that the concurrent administration of ATRA plus chemotherapy, compared to ATRA alone, for induction followed by consolidation reduces the incidence of the RAS (18 versus 9.2%, respectively), and reduces the mortality rate (2.5 versus 0.5%. respectively).12 Another serious toxic effect of ATRA treatment, characterized by variable association of severe headache, nausea and vomiting, visual changes, pailledema and retinal haemorrhages, associated or not with RAS and/or leukocytosis, was reported in 1993 by Mahmoud et al as Pseudotumor cerebri.13 This toxicity appears more frequent among paediatric patients.
LATE PHASE II STUDIES OF ATRA IN APL To avoid or reduce the toxicity observed in early phase II studies, late phase II studies have evaluated the role of adding or combining standard chemotherapeutic induction regimens to ATRA or the reduction of ATRA dosage. Table 2 summarizes the remission
Table 2. ATRA ^ chemotherapy as induction treatment in APL patients (late phase II studies). Reference
Year
ATRA (mg/m2)
Number of patients
CR(%)
14 15 16 17 18
1992 1993 1993 1995 1996
45 45 25 45 45
26 64 30 109 20
96 84 80 89 90
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rates obtained in these studies. In the study of Fenaux et al14, 26 patients with newly diagnosed APL were treated with ATRA (45 mg/m2/day) until complete remission. ATRA was followed by an intensive course of induction chemotherapy in which daunorubicin (DNR) was given for 4 days in combination with continuous infusion for 7 days of Ara-C (‘4 þ 7’ course). Then, patients in CR received, as consolidation, three ‘2 þ 5’ DNR þ Ara C followed by maintenance chemotherapy. However, if hyperleukocytosis rapidly developed, the ‘4 þ 7’ course was administered in emergency. Although CR was achieved by 25 (96%) patients, only 14 achieved CR with ATRA alone whereas in 11 patients CR was achieved after the addition of the ‘4 þ 7’ course on day 2– 30 of treatment, mainly because of rapidly increased leukocytes above 10 000/ml. Apart from hyperleukocytosis, side-effects were usually moderate. The comparison of these results with those obtained in a previous trial—in which chemotherapy alone was utilized to treat newly diagnosed APL—revealed significant differences for disease-free and eventfree survival (P ¼ 0:02 and P ¼ 0:006, respectively), but not for CR rate ðP ¼ 0:08Þ; suggesting that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, more importantly, by reducing the relapse rate. Investigators in Japan treated 64 evaluable APL patients with 45 mg/m2/day ATRA in two multi-institutional prospective studies.15 In contrast to the previous French study, only seven of these patients were newly diagnosed, while the remaining 57 were: refractory to initial induction ðn ¼ 21Þ or salvage ðn ¼ 10Þ chemotherapy or in first ðn ¼ 17Þ; second ðn ¼ 5Þ and third ðn ¼ 4Þ relapse, respectively. Despite that, 84% of patients obtained CR and received standard consolidation and maintenance chemotherapy. Toxicity attributable to ATRA was minimal, and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage and elevated serum triglyceridaemia. To reduce the incidence of toxic effects related to ATRA, Castaigne et al had utilized a reduced dosage of ATRA in 30 APL patients, of whom 12 were newly diagnosed.16 The ATRA dose was 25 mg/m2/day until CR; 24/30 patients (80%) achieved CR, three failed, and three died before day 30. However, despite this reduced dosage, there were no differences in terms of therapeutic efficacy, triggering of hyperleukocytosis, or severe toxicity and pharmacokinetic results with ATRA at 25 or 45 mg/m2/day. In 1995 the Japan Adult Leukaemia Study Group published a multi-centre trial comparing ATRA for newly diagnosed APL with a previous Japanese study in which APL patients were treated with standard intensive chemotherapy.17 Of the 110 patients who were entered into the study only 28 (25%) received ATRA alone; of these, 25 (89%) achieved CR. Of the remaining 82 patients, one died before the initiation of treatment and 72/81 (89%) achieved CR, so that the overall CR rate was 89%. Compared to the previous study in which APL patients were treated only with chemotherapy, there was a highly significant difference in remission rate ðP ¼ 0:004Þ; EFS ðP ¼ 0:0007Þ; and also early mortality rate ðP ¼ 0:02Þ: As for toxicity, only 7/110 (6.3%) developed RAS, with one death. Other toxicity associated with ATRA included cheilitis, desquamation, muscle pain and hypertriglyceridaemia. The results of the previous studies demonstrated that ATRA, with or without chemotherapy, leads to an improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL. However, many of the patients who had achieved CR in these studies had also required the addition of standard chemotherapy. Therefore, to avoid the risk that APL patients, depending on the number of white blood cells or blasts, received a different type of treatment, the Italian co-operative group GIMEMA began, in March 1993, a pilot study named AIDA combining ATRA with idarubicin (IDA) for treating newly diagnosed APL patients.18
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ATRA was administered orally beginning on the first day of induction at a dosage of 45 mg/m2/day until complete remission (CR), whereas IDA was administered intravenously at a dosage of 12 mg/m2/day on days 2, 4, 6 and 8 of the induction. Patients who achieved CR were consolidated with three courses of chemotherapy without ATRA. They were then followed up for molecular and haematological CR. Of the 20 consecutive, newly diagnosed patients among 13 participating institutions, four (two with M3v) had leukocyte counts . 10 000/ml. Sixteen patients (80%) were tested for the presence of the PML – RARa hybrid gene at diagnosis by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were found to be RT-PCRþ for the hybrid gene. In the remaining four patients, the cytogenetic study showed the presence of the t(15;17) translocation. CR was achieved by 18/20 (90%) patients after a median time of 36 days; the remaining two patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive haemoptysis, respectively. RAS was observed in only two (10%) patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered. However, after recovering, one patient achieved CR, whereas the other died at day 34 because of massive haemoptysis. Other side-effects were very limited. Interestingly, during recovery from the third consolidation course, only three of 14 (21.4%) tested patients were RT-PCRþ for the PML – RARa hybrid gene. Of these, two relapsed shortly afterwards, whereas the PML – RARa disappeared in the last patient at successive testing performed 2 months later. The results of this study indicated for the first time that: (1) after three consolidation courses, the majority of patients who achieved CR were RT-PCR-negative for the hybrid gene PML –RARa; (2) the persistence of RT-PCR positivity for the PML – RARa hybrid gene after 3 consolidation courses was indicative of early relapse, thus suggesting that these patients still required additional treatment. Summarizing the results obtained in these phase II studies, it was evident that the introduction of ATRA in the treatment of this peculiar subtype of acute myeloid leukaemia had improved its outcome rather in terms of CR rate than in terms of EFS. As a consequence, many investigators initiated phase III or randomized studies to define more accurately the role of ATRA in APL as well as the best way to combine ATRA with standard chemotherapy.
PHASE III STUDIES OF ATRA IN APL With the exclusion of the AIDA pilot study, in which ATRA was combined to IDA alone during induction, all the other phase II studies have utilized as chemotherapy a combination of DNR þ Ara-C. However, even in the AIDA protocol, consolidation courses contained Ara-C. Therefore, to determine the effect of omission of Ara-C from the entire treatment of newly diagnosed APL, Estey and colleagues19, conducted a study in which induction consisted of ATRA (45 mg/m2/day until CR) and IDA 12 mg/m2/day for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2/day for 3 days and then, for 2 years after CR, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2/day for 2 days. The results obtained were compared with those obtained in a historic group of newly diagnosed APL patients given Ara-C with either doxorubicin, amsacrine (AMSA) or daunorubicin without ATRA. The CR rate in the ATRA þ IDA group was 77% and was not
ATRA in APL 425
significantly different from the historic rate. In contrast, a superior overall DFS for the ATRA þ IDA group was registered ðP ¼ 0:03Þ:19 A propsective study omitting Ara-C and utilizing a modified AIDA protocol was published 2 years later by the Spanish co-operative group PETHEMA.20 Newly diagnosed PML –RARa-positive APL were treated with the original AIDA regimen, except for the omission of cytarabine and etoposide from consolidation. Maintenance therapy consisted of 90 mg/m2/day mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and, intermittently, 45 mg/m2/day ATRA for 15 days every 3 months. Of the 123 patients enrolled with newly diagnosed PML –RARa-positive APL, 109 achieved CR (89%), 12 died of early complications, and the remaining two were resistant. Consolidation treatment was associated with very low toxicity and no deaths in remission were recorded. Molecular assessment of response by RT-PCR showed conversion to PCR-negative in 48 of 99 (51%) and 82 of 88 patients (93%) after induction and consolidation, respectively. The 2-year overall survival and EFS were 82 and 79%, respectively. For patients who achieved CR, the 2-year disease-free survival (DFS) was 92%. These data indicated that the omission of Ara-C and etoposide from the original AIDA protocol did not apparently compromise the anti-leukaemic effect, suggesting a minor role for these two drugs in the treatment of newly diagnosed PML – RARa-positive APL patients. An indirect and partial confirmation of both of these results, suggesting that Ara-C can be easily eliminated from the APL treatment protocols, was recently derived from the randomized GIMEMA trial conducted in the pre-ATRA era comparing IDA þ AraC with IDA alone during induction. The results of this study have clearly indicated that IDA monochemotherapy during induction favourably influences the duration of EFS in patients with newly diagnosed hypergranular APL.21
RANDOMIZED STUDIES The first randomized study comparing standard chemotherapy (DNR þ Ara-C) with ATRA followed by the same chemotherapeutic protocol (ATRA group) was the APL 91. Early termination of this trial occurred after the first interim analysis, as EFS was significantly higher in the ATRA group, even though the difference in CR rate between the two groups was not significant.22 As a consequence, the authors suggested that ATRA should be incorporated in the frontline therapy of newly diagnosed APL. The long-term follow-up of this study confirms the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL. In particular, EFS and relapse rate at 4 years were 63 and 31% in the ATRA group, as compared to 17 and 78% in the chemotherapy group (P ¼ 0:0001 and relative risk 2.95, P ¼ 0:0001 and relative risk 3.68, respectively).23 However, despite these results, it was not yet demonstrated whether induction therapy with ATRA alone was superior to chemotherapy alone in newly diagnosed APL. This question was addressed in the randomized study of the North American Intergroup.24 In this study, 346 patients with previously untreated APL were randomly assigned to receive ATRA or DNR þ Ara-C as induction treatment. Patients who had a CR received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy followed by high-dose Ara-C þ DNR. Those patients still in CR after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with ATRA or to observation. CR was obtained by 69% of the patients who had been treated with chemotherapy as compared to 72% of those
426 G. Avvisati and M. S. Tallman
receiving ATRA alone ðP ¼ 0:56Þ: ATRA as induction or maintenance treatment significantly improved disease-free and overall survival as compared with chemotherapy alone. The updated results of this study confirmed that ATRA as induction or maintenance treatment significantly improved disease-free and overall survival as compared with chemotherapy alone. In particular, the 5-year DFS was 16% for patients randomized to DNR þ Ara-C followed by observation, 47% for DNR þ Ara-C followed by ATRA maintenance, 55% for those randomized to ATRA as induction followed by observation, and 74% for the patients randomized to ATRA in induction and maintenance (Figure 1).25 A more complex randomized study was published in 1999 by the European APL Group. In this study, 413 newly diagnosed patients were randomized to two induction schedules: ATRA followed by chemotherapy (CT) and ATRA þ CT, with CT added on day 3 of ATRA treatment. Induction treatment was stratified on white blood cell (WBC) count and age. All patients achieving CR received two additional DNR-Ara-C courses (only one in patients 66 –75 years of age) and were then randomized to one of four maintenance regimens. Overall, 92% of the patients achieved CR, 7% had an early death, and only one patient had leukaemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in five cases. Although the CR rate was similar in all 1.0
Probability
0.8
0.6 0.4 0.2 0.0 0
1
2
3
4
5
6
7
8
9
Years Group DA/ATRA DA/Obs ATRA/ATRA ATRA/Obs
0-2 18/50 40/51 11/49 20/54
Time Interval 2-4 4-6 6-8 6/28 0/18 0/8 1/8 0/6 0/2 1/34 0/26 0/9 2/32 1/24 1/12 (no. events/no. at risk)
Figure 1. Kaplan-Meier product-limit estimates of disease-free survival based on both the induction and maintenance randomizations in the long-term outcome of the North American Intergroup protocol. DA/ATRA ¼ DNR þ Ara-C as induction followed by ATRA as maintenance; DA/Obs ¼ DNR þ Ara-C as induction followed by observation; ATRA/ATRA ¼ ATRA as induction followed by ATRA as maintenance; ATRA/Obs ¼ ATRA as induction followed by observation. Reproduced from Tallman MS et al (All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100: 4298– 4302). Copyright American Society of Hematology, used with permission.
ATRA in APL 427
induction treatment groups, relapse at 2 years was estimated at 6% in the ATRA þ CT group, versus 16% in the ATRA followed by CT group (P ¼ 0:04; relative risk ¼ 0.41). Two hundred and eighty-nine patients were randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous lowdose CT (6 mercaptopurine þ methotrexate) for 2 years, or both, using a 2-by-2 factorial design. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT ðP ¼ 0:0002Þ and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA ðP ¼ 0:02Þ: An additive effect of continuous maintenance CT and intermittent ATRA was observed, and only six of the 74 patients who received both maintenance treatments relapsed. Therefore, results of this study indicated that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA by reducing the incidence of relapse in APL significantly improved survival.26 To determine the optimal timing and duration of ATRA treatment, the Medical Research Council (MRC) randomized patients with morphologically defined APL to receive a 5-day course of ATRA before commencing CT or to receive daily ATRA commencing with CT and continuing until CR.27 Treatment with extended ATRA resulted in a superior remission rate (87 versus 70%, P , 0:001), due to fewer early and induction deaths (12 versus 23%, P ¼ 0:02), and less resistant disease (2 versus 7%, P ¼ 0:03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20 versus 36% at 4 years, P ¼ 0:04) and resulted in superior survival (71 versus 52 at 4 years, P ¼ 0:005). However, presenting white blood cell count (WBC) , 10 000/ml was a key determinant of outcome. In fact, APL patients who presented with WBC , 10 000/ml had substantial benefit from combining ATRA with induction chemotherapy until remission, whereas patients with a higher WBC did not benefit.
THE ROLE OF MAINTENANCE The role of maintenance treatment, with or without ATRA, in APL has been evaluated by the North American Intergroup24,25 and the European APL ‘9326 trials. Both trials have shown that including ATRA-containing maintenance in the treatment programme gives an advantage in terms of DFS24,25 and relapse rate.26 This issue has also been evaluated by the GIMEMA group which adopted the same four randomization arms of the European APL Group (ATRA versus chemotherapy versus ATRA þ chemotherapy versus observation). However, in contrast to the European APL Group, in the GIMEMA study, only those patients who were found to be RT-PCR-negative for the PML –RARa hybrid gene at the end of three consolidation courses were further randomized.28 This study is currently under evaluation and results will be available soon; however, preliminary data do not confirm the results of the European APL group and American Intergroup (Avvisati G., personal data).
RESISTANCE TO ATRA Primary resistance in PML– RARa-positive APL is rare, and CR can be achieved by almost all ATRA-treated APL patients with a genetically confirmed PML– RARa
428 G. Avvisati and M. S. Tallman
chimeric gene. However, once CR was achieved, the continuous use of ATRA alone produced the appearance of resistance to this drug in the totality of patients with subsequent relapse.29 Subsequently, it was demonstrated that secondary acquired ATRA resistance occurs also in patients who relapsed from regimens combining ATRA and chemotherapy, despite limited ATRA exposure. Therefore, it was suggested that an adaptive hypercatabolic response to pharmacological ATRA levels was the principal mechanism of ATRA resistance.30,31 However, considering that the intermittent administration of ATRA32 or of alternative retinoic formulations such as 9-cys retinoic acid33, Am8034 and liposomal ATRA35,36, was able to bypass this hypercatabolic reaction, hypercatabolism was considered only partially responsible for ATRA resistance. Alternatively, it has been hypothesized that the mechanisms responsible for this resistance were APL cellular alterations limiting the access of the drug to the cell nucleus by cytoplasmic sequestration.37 However, this hypothesis has not been confirmed38, and recent studies suggest that molecular disturbances in APL cells have a predominant role—particularly if disease relapse occurs a few months after discontinuing ATRA therapy39,40 (for a review see Ref. 41).
THE PROGNOSTIC FACTORS Although the introduction of ATRA has greatly improved the CR rate, as well as the overall survival of APL patients, by rapidly ameliorating the severe coagulopathy present in APL at diagnosis, there are still patients dying of fatal haemorrhages.42,43 Therefore, in patients with genetically proven APL who receive ATRA associated with anthracycline-containing chemotherapy, risk factors for CR which, by extension, influence the event-free survival (EFS), include older age and elevated white blood cell count.27,44 Other features affecting the early death rate are the presence of purpura and low platelet number at diagnosis.44 As to the duration of remission and the risk of relapse, white blood cell count above 10 000/ml at presentation was the only factor which correlated with increased risk of relapse in all reported series.23,27,44,45 In addition, both the European APL ‘9123 and a combined analysis of the GIMEMA and PETHEMA groups45 indicated that initial platelet number below 50 £ 109/l or 40 £ 109/l, respectively, also negatively affected the risk of relapse. In particular, a platelet number below 40 £ 109/l was an independent variable associated with increased risk of relapse in the combined GIMEMA and PETHEMA study.45 Several biological characteristics have been analysed for their effect on prognosis. Two recent studies indicated that CD56 may be associated with inferior outcome.46,47 Regarding secondary cytogenetic abnormalities, these do not seem to confer inferior outcome.48 A trend towards inferior outcome was also suggested for patients with the short (or bcr3) PML – RARa isoform as compared to cases with the more frequent long type (or bcr1 – 2). However, except for an early study in patients treated with ATRA alone49, the association of the bcr3 isoform with poorer outcome was not statistically significant in all recent ATRA þ chemotherapy trials.6,27,45,50,51 Slow kinetics of molecular remission, and persistence or conversion to PCR-positive for the PML – RARa after consolidation, has been correlated with increased risk of haematological relapse.27 Finally, internal tandem duplications in the FLT3 gene appear to be associated with an unfavourable prognosis.52
ATRA in APL 429
EXTRAMEDULLARY DISEASE Recent studies and anecdotal reports have suggested that, among patients treated with ATRA, there may be an increased incidence of extramedullary disease, particularly in the central nervous system.53 – 57 It is possible that ATRA perturbs adhesion molecules predisposing to extramedullary disease. Alternatively, the omission of high-dose Ara-C from contemporary therapeutic strategies may play a role.
CONCLUSIONS The data obtained from large co-operative groups indicate that the combination of ATRA and chemotherapy during induction phase results in a CR rate of more than 90%. Moreover, it is worth noting that, when a molecular diagnosis of APL is provided, resistance is rarely observed, suggesting at least an additive effect of ATRA and chemotherapy in treating APL patients. The analyses of the European APL group trial and of the MRC trial confirm that induction treatment combining ATRA and chemotherapy can consistently yield CR rates . 90% on a large multi-centre basis, and suggest, in terms of relapse, a benefit for chemotherapy given concurrently with ATRA treatment.26,27 Alternatively, if an additive effect exists, one should consider the possibility that reduced chemotherapy regimens could be sufficient to induce CR when combined with ATRA, as recently reported by the Spanish co-operative group PETHEMA. Thus, the association of ATRA and a short course of induction chemotherapy appears to be highly effective in inducing CR and reducing toxicity. Moreover, by reducing the toxicity related to the induction therapy, treatment can be intensified during post-remission. In conclusion, from the studies utilizing ATRA for treating APL: 1. The response to ATRA is dependent on the presence of the hybrid gene PML – RARa. Therefore, a morphological diagnosis of APL must always be confirmed by molecular and/or cytogenetic analysis. 2. A concurrent administration of ATRA and chemotherapy is better than a sequential administration of ATRA after chemotherapy. 3. In contrast to other AMLs, the induction treatment of APL using ATRA-based protocols does not seem to require the use of Ara-C, when an adequate dose of anthracycline is administered. Data suggest that Ara-C may also be omitted from consolidation, although long-term results of these trials are required to clarify this issue. 4. Once CR is achieved, patients must be consolidated with at least two cycles of standard consolidation regimens.
Practice points † all-trans retinoic acid (ATRA) should be incorporated in the treatment of all patients with APL † the retinoic acid syndrome (RAS) constitutes the most important and lifethreatening complication of ATRA therapy
430 G. Avvisati and M. S. Tallman
† early recognition of RAS and institution of dexamethasone, is mandatory and usually results in complete resolution of the syndrome † the concurrent administration of ATRA and chemotherapy for induction appears to decrease the relapse compared to ATRA for induction † maintenance therapy with ATRA, with or without low-dose chemotherapy, is beneficial † the achievement of a molecular negative status, RT-PCR for the PML –RARa fusion transcript, is the desired therapeutic endpoint
Research agenda † decrease the early mortality rate resulting from haemorrhage † identify ways of preventing the retinoic acid syndrome † continue to identify patients at particularly low or high risk of relapse in order to tailor therapy † complete long-term randomized study (currently ongoing) to determine whether Ara-C can be excluded from induction and/or consolidation
REFERENCES 1. Bollag W & Holdener EE. Retinoids in cancer prevention and therapy. Annals of Oncology 1992; 3: 513–526. * 2. Huang ME, Ye YC, Chen SR et al. Use of all trans-retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567 –572. 3. Castaigne S, Chomienne C, Daniel MT et al. All trans-retinoic acid as a differentiation therapy for acute promyelocytic leukemia: I. Clinical Results. Blood 1990; 76: 1704– 1709. * 4. Warrell Jr. RP, Frankel SR, Miller Jr. WH et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all trans-retinoic acid). New England Journal of Medicine 1991; 324: 1385–1393. 5. Chen ZX, Xue YQ, Zhang R et al. A clinical and experimental study on all trans-retinoic acid-treated acute promyelocytic leukemia patients. Blood 1991; 78: 1413– 1419. 6. White KL, Wiley JS, Frost T et al. All-trans retinoic acid in the treatment of acute promyelocytic leukaemia. Australia New Zealand Journal of Medicine 1992; 22: 446–448. 7. Hernandez P, Carnot J, Dorticos E et al. All-trans retinoic acid in acute promyelocytic leukemia: preliminary results in Cuba. Annals of Hematology 1992; 65: 121–123. 8. Frankel SR, Eardley A, Heller G et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Annals of Internal Medicine 1994; 120: 278–286. * 9. Frankel SR, Eardley A, Lauwers G et al. The retinoic acid syndrome in acute promyelocytic leukemia. Annals of Internal Medicine 1992; 117: 292 –296. 10. de Botton S, Dombret H, Sanz M et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL group. Blood 1998; 92: 2712– 2718. 11. Tallman MS, Andersen JW, Schiffer CA et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000; 95: 90– 95. 12. de Botton S, Chevret S, Coiteux V et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia 2003; 17: 339–342. 13. Mahmoud HH, Hurwitz CA, Roberts WM et al. Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 1993; 342: 1394–1395. 14. Fenaux P, Castaigne S, Dombret H et al. All-trans retinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood 1992; 80: 2176–2181.
ATRA in APL 431 15. Ohno R, Yoshida H, Fukutani H et al. Multi-institutional study of all-trans retinoic acid as a differentiation therapy of refractory acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare. Leukemia 1993; 7: 1722–1727. * 16. Castaigne S, Lefebvre P, Chomienne C et al. Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2)in acute promyelocytic leukemia. Blood 1993; 82: 3260– 3264. 17. Kanamaru A, Takemoto Y, Tanimoto M et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukaemia Study Group. Blood 1995; 85: 1202–1206. 18. Avvisati G, Lo Coco F, Diverio D et al. AIDA (all-trans retinoic acid þ idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) pilot study. Blood 1996; 88: 1390–1398. 19. Estey E, Thall PF, Pierce S et al. Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine. Journal of Clinical Oncology 1997; 15: 483– 490. 20. Sanz MA, Martin G, Rayon C et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukaemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999; 94: 3015–3021. 21. Avvisati G, Petti MC, Lo Coco F et al. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood 2002; 100: 3141– 3146. 22. Fenaux P, Le Deley MC, Castaigne S et al. Effect of all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL91 Group. Blood 1993; 82: 3241–3249. 23. Fenaux P, Chevret S, Guerci A et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia 2000; 14: 1371–1377. * 24. Tallman MS, Andersen JW, Schiffer CA et al. All-trans retinoic acid in acute promyelocytic leukemia. New England Journal of Medicine 1997; 337: 1201– 1208. 25. Tallman MS, Andersen JW, Schiffer CA et al. All-trans retinoic acid in acute promyelocytic leukemia: longterm outcome and prognostic factor analysis from the North America Intergroup protocol. Blood 2002; 100: 4298–4302. * 26. Fenaux P, Chastang C, Chevret S et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94: 1192–2000. * 27. Burnett AK, Grimwade D, Solomon E et al. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood 1999; 93: 4131–4143. * 28. Mandelli F, Diverio D, Avvisati G et al. Molecular remission in PML/RARa-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997; 90: 1014–1021. 29. Muindi JM, Frankel S, Miller Jr. WH et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid resistance in patients with acute promyelocytic leukemia. Blood 1992; 79: 299–303. 30. Muindi J, Frankel S, Huselton C et al. Clinical pharmacology of oral all-trans retinoic acid with acute promyelocytic leukemia. Cancer Research 1992; 52: 2138–2142. 31. Adamson P, Pitot H, Balis F et al. Variability in the oral bioavailability of all-trans-retinoic acid. Journal of the National Cancer Institute 1993; 85: 993 –996. 32. Adamson PC, Bailey J, Pluda J et al. Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. Journal of Clinical Oncology 1995; 13: 1238– 1241. 33. Miller Jr. WH, Jakubowski A, Tong WP et al. 9-cys retinoic acid induces complete remission but does not reverse clinical acquired retinoid resistance in acute promyelocytic leukemia. Blood 1995; 85: 3021–3027. 34. Tobita T, Takeshita A, Kitamura K et al. Treatment with a new synthetic retinoid, Am 80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood 1997; 90: 967–973. 35. Estey E, Thall PF, Mehta K et al. Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid. Blood 1996; 87: 3650–3654. 36. Douer D, Estey E, Santillana S et al. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood 2001; 97: 73–80. 37. Delva L, Cornic M, Balitrand N et al. Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro sensitivity and cellular retinoic binding protein levels in leukemic cells. Blood 1993; 82: 2175–2181. 38. Zhou D-C, Hallam SJ, Klein RS et al. Constitutive expression of cellular retinoic acid binding protein II and lack of correlation with sensitivity to all-trans retinoic acid in acute promyelocytic leukemia cells. Cancer Research 1998; 58: 5770–5776.
432 G. Avvisati and M. S. Tallman 39. Ding V, Li YP, Nobile LM et al. Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARalpha fusion gene after relapse of acute promyelocytic leukaemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood 1998; 92: 1172–1183. 40. Zhou D-C, Kim SH, Ding V et al. Frequent mutations in the ligand-binding domain of PML–RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to alltrans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood 2002; 99: 1356– 1363. 41. Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. Leukemia 2002; 16: 1940–1958. 42. Barbui T, Finazzi G & Falanga A. The impact of all-trans retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood 1998; 91: 3093–3102. 43. Di Bona E, Avvisati G, Castaman G et al. Early hemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. British Journal of Haematology 2000; 108: 689–695. 44. Asou N, Adachi J, Tamura J et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Journal of Clinical Oncology 1998; 16: 78– 85. * 45. Sanz M, Lo Coco F, Martin G et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and the GIMEMA cooperative groups. Blood 2000; 96: 1247–1253. 46. Murray CK, Estey E, Paietta E et al. CD56 expression in acute promyelocytic leukemia: a possible indicator of poor treatment outcome? Journal of Clinical Oncology 1999; 17: 293 –297. 47. Ferrara F, Morabito F, Martino B et al. CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous ATRA and chemotherapy. Journal of Clinical Oncology 2000; 18: 1295–1300. * 48. Slack JL, Arthur DC, Lawrence D et al. Secondary cytogenetic changes in acute promyelocytic leukemiaprognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. Journal of Clinical Oncology 1997; 15: 1786–1795. 49. Vahdat L, Maslak P, Miller WH et al. Early mortality and retinoic acid syndrome in acute promyelocytic leukemia: impact of leucocytosis, low-dose chemotherapy, PML/RAR( isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 1994; 84: 3843–3849. 50. Fukutani H, Naoe T, Ohno R et al. Isoforms of PML–retinoic acid receptor alpha fused transcripts affect neither clinical features of acute promyelocytic leukemia nor prognosis after treatment with all-trans retinoic acid. Leukemia 1995; 9: 1478–1482. 51. Gallagher RE, Willman CL, Slack JL et al. Association of PML/RAR( fusion mRNA type with pre-treatment characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood 1997; 90: 1656–1663. 52. Noguera NI, Breccia M, Divona M et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002; 16: 2185–2189. 53. Ko BS, Tang JL, Chen YC et al. Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia—the occurrence of retinoic acid syndrome is a risk factor. Leukemia 1999; 13: 1406–1408. 54. Tobita T, Shinjyo K, Yanagi M et al. Relapse in the external auditory canal of acute promyelocytic leukemia after treatment with all-trans retinoic acid. Internal Medicine 1997; 36: 484–486. 55. Wiernik PH, De Bellis R, Muxi P et al. Extramedullary acute promyelocytic leukemia. Cancer 1996; 79: 2510–2514. 56. Weiss MA & Warrell Jr RP. Two cases of extramedullary acute promyelocytic leukemia. Cytogenetics, molecular biology, and phenotypic and clinical studies. Cancer 1994; 74: 1882–1886. 57. Specchia G, Lo Coco F, Vignetti M et al. Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell’Adulto. Journal of Clinical Oncology 2001; 19: 4023– 4028.
6 All-trans retinoic acid in acute promyelocytic leukaemia Giuseppe Avvisati*
MD, PhD
Hematology, University Campus Bio-Medico, Via Emilio Longoni 83, Roma 00159, Italy
Martin S. Tallman
MD
Hematology– Oncology, Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago,USA
The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed. Key words: all-trans retinoic acid; acute promyelocytic leukaemia.
All-trans retinoic acid (ATRA) belongs to a class of chemical compounds structurally related to vitamin A and is one of the class of compounds known as retinoids. Some of these compounds, including vitamin A, have shown limited success in the prevention of cancer and anti-cancer therapy. The mechanism of action of retinoids in chemoprevention and therapy of cancers involves modulation of cell proliferation and differentiation. In fact, retinoids are capable of both inhibiting cell proliferation and inducing cell differentiation. These activities have been demonstrated particularly in haematopoietic and epithelial transformed cell lines.1 A direct consequence of these experimental data has been the use of ATRA in the induction treatment of acute promyelocytic leukaemia (APL). The incorporation of ATRA into the therapy of APL was the most significant step forward in the 25 years of treatment and prognosis of acute myeloid leukaemias; it produced dramatic therapeutic effects on APL, leading to very high rates of complete remission (CR) and cure. * Corresponding author. Tel.: þ39-06-2254-1749; Fax: þ39-06-2254-1456. E-mail address: [email protected] 1521-6926/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
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EARLY PHASE II STUDIES OF ATRA IN APL The use of ATRA in APL as a single therapeutic agent was pioneered in the late 1980s by investigators in China. Twenty-four APL patients were treated with 45 to 100 mg/m2/day of ATRA. Of these, eight patients had been either non-responsive or resistant to previous chemotherapy and the remaining 16 patients were previously untreated. All except one of the patients achieved complete remission with ATRA alone, without developing bone marrow hypoplasia. The study of bone marrow suspension cultures in 15/24 patients revealed that 14 of these patients had morphological maturation in response to the retinoic acid. The only patient not responding to retinoic acid in vitro was resistant to treatment with retinoic acid but achieved complete remission after addition of low-dose cytosine arabinoside (Ara-C). During the course of therapy, none of the patients showed any progresses in abnormal coagulation parameters. The only side-effects observed were mild dryness of the lips and skin, with occasional headaches and digestive symptoms. However, despite the high remission rate, eight patients relapsed after only 2 –5 months of complete remission.2 The second report on the use of ATRA in APL was that of the French investigators who treated 22 APL patients with 45 mg/m2/day for a total of 90 days. Although only 4/22 were newly diagnosed, 14 achieved complete remission without bone marrow (BM) hypoplasia through a differentiation effect of treatment, as suggested by the presence of Auer rods in the maturing cells. Moreover, at remission, the t(15;17) initially present in 20 patients was not found. Skin and mucosal dryness, hypertriglyceridaemia, and an increase in hepatic transaminase were frequently observed. Eleven patients had bone pain while four patients had hyperleukocytosis. Maintenance treatment with low-dose chemotherapy or ATRA did not prevent early relapses.3 Following these results, a tremendous interest in the clinical use of ATRA in APL was generated. As a consequence, since then, several groups have begun to utilize this therapeutic agent in relapsed as well as newly diagnosed APL patients. A summary of these early phase II studies is reported in Table 1. In particular, the study of Warrell et al indicated, for the first time, that clinical response to ATRA in APL was linked to the expression of an aberrant RARa (retinoic acid receptor-a) nuclear receptor and that its molecular detection could be a useful marker for detecting residual leukaemia in APL patients.4 In the study of Chen et al, the very high rate of complete remission (CR)—94%— was followed by a relapse rate of about 40%. However, patients who relapsed after
Table 1. ATRA alone as induction treatment in APL patients (early phase II studies). Reference
Year
ATRA mg/m2
2 3 4 5 6 7 8
1988 1990 1991 1991 1992 1992 1994
45–100 45 45 60–80 45 50 45
Number of patients
CR(%)
24 22 11 50 11 7 51
96 64 82 94 64 71 86
ATRA in APL 421
a chemotherapy-maintained CR could be effectively re-induced into second CR by ATRA. However, if relapse occurred after a CR maintained by both ATRA and chemotherapy, the sensitivity of newly emerged leukaemic clones to ATRA was greatly reduced. As a consequence, these investigators suggested that ATRA should be replaced by conventional chemotherapy as soon as CR is achieved.5 Finally, the study of Frankel et al concluded that ATRA was an effective agent in inducing remission in patients with a molecular diagnosis of APL, but that remissions were short and resistance developed rapidly. However, ATRA followed by consolidation chemotherapy was associated with longer survival times when compared with historical controls treated only with chemotherapy.8 From these early phase II studies, in which ATRA had been utilized as single induction agent, it was evident that, compared with standard chemotherapy, ATRA acted as a specific differentiative agent on leukaemic promyelocytes, inducing higher rates of CR, ranging from 64 to 100%, without causing bone marrow hypoplasia or exacerbation of the coagulopathy. Moreover, the toxicity was very different from that caused by standard chemotherapy. The toxicity ranged from occasionally severe hyperleukocytosis to skin and mucosa dryness, hypertriglyceridaemia, and an increase in hepatic transaminases. In some cases hyperleukocytosis was associated with severe bone pain, weight gain, dyspnoea, headache and fever.
THE DEFINITION OF RETINOIC ACID SYNDROME AND OF PSEUDOTUMOUR CEREBRI The most serious adverse effect during the induction treatment with ATRA was the appearance of a syndrome primarily characterized by fever and respiratory distress. Additional signs and symptoms included weight gain, lower extremity oedema, pleural or pericardial effusions, and episodic hypotension. This syndrome was named retinoic acid syndrome (RAS) by Frankel et al.9 These investigators had reported a total of nine of 35 APL patients treated with ATRA in whom this symptom complex occurred from 2 to 21 days after starting treatment. Post-mortem examinations in two of the three patients who died showed pulmonary interstitial infiltration with maturing myeloid cells. In 6/9 cases, the onset of the syndrome was preceded by an increase in peripheral blood leukocytes. Leukapheresis, temporary cessation of therapy with ATRA, and cytotoxic chemotherapy in moderate doses were not useful once respiratory distress was established. However, the administration of high-dose corticosteroid (dexamethasone) therapy early in the course of the syndrome in four of these patients resulted in prompt symptomatic improvement and full recovery in three patients. Therefore, early recognition of the symptom complex of fever and dyspnoea, combined with prompt corticosteroid treatment, may decrease morbidity and mortality associated with this syndrome. Since this initial description, however, no large series of RAS have been reported in detail until 1998 when Fenaux et al described 64 (15%) of the 413 patients included in the European APL group trial who experienced RAS during induction treatment.10 In this series, the main clinical signs were: respiratory distress (89%), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), hypotension (12%); 63 of the 64 patients had at least three of these signs, which developed after a median of 7 days. Thirteen patients required mechanical ventilation, and RAS was responsible for death in only five cases (1.2% of the total number of patients treated). Moreover, 86% of these
422 G. Avvisati and M. S. Tallman
64 patients achieved CR. Noteworthy, none of these patients who received ATRA for maintenance developed recurrent RAS. However, in this study, the occurrence of RAS was associated with lower event-free survival (EFS) and survival. The incidence, clinical course, and outcome of patients with newly diagnosed APL who developed RAS was also recently reported by the investigators participating in the North American Intergroup Protocol.11 Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome after a median time of 11 days of ATRA (range, 2 – 47). The median WBC count was 31 000/ml at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and was resumed in 19/36 patients (53%) with recurrence of RAS in three and one death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and eight achieved complete remission (CR). Among seven patients in whom ATRA was not re-started, and who were not treated with chemotherapy, five achieved CR and two died. In 8/44 patients in whom ATRA was not discontinued, subsequent resolution of the syndrome was observed in seven. Two deaths were definitely attributable to the syndrome, and no patient receiving ATRA as maintenance developed the syndrome. From these descriptions concerning the incidence and outcome of RAS in large cooperative trials it appears that, despite its incidence of 15 –25%, when recognized early and treated, the death rate is very low and none of the patients who experienced RAS had recurrence when ATRA was administered as maintenance. A recent analysis of the European APL 93 trial suggests that the concurrent administration of ATRA plus chemotherapy, compared to ATRA alone, for induction followed by consolidation reduces the incidence of the RAS (18 versus 9.2%, respectively), and reduces the mortality rate (2.5 versus 0.5%. respectively).12 Another serious toxic effect of ATRA treatment, characterized by variable association of severe headache, nausea and vomiting, visual changes, pailledema and retinal haemorrhages, associated or not with RAS and/or leukocytosis, was reported in 1993 by Mahmoud et al as Pseudotumor cerebri.13 This toxicity appears more frequent among paediatric patients.
LATE PHASE II STUDIES OF ATRA IN APL To avoid or reduce the toxicity observed in early phase II studies, late phase II studies have evaluated the role of adding or combining standard chemotherapeutic induction regimens to ATRA or the reduction of ATRA dosage. Table 2 summarizes the remission
Table 2. ATRA ^ chemotherapy as induction treatment in APL patients (late phase II studies). Reference
Year
ATRA (mg/m2)
Number of patients
CR(%)
14 15 16 17 18
1992 1993 1993 1995 1996
45 45 25 45 45
26 64 30 109 20
96 84 80 89 90
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rates obtained in these studies. In the study of Fenaux et al14, 26 patients with newly diagnosed APL were treated with ATRA (45 mg/m2/day) until complete remission. ATRA was followed by an intensive course of induction chemotherapy in which daunorubicin (DNR) was given for 4 days in combination with continuous infusion for 7 days of Ara-C (‘4 þ 7’ course). Then, patients in CR received, as consolidation, three ‘2 þ 5’ DNR þ Ara C followed by maintenance chemotherapy. However, if hyperleukocytosis rapidly developed, the ‘4 þ 7’ course was administered in emergency. Although CR was achieved by 25 (96%) patients, only 14 achieved CR with ATRA alone whereas in 11 patients CR was achieved after the addition of the ‘4 þ 7’ course on day 2– 30 of treatment, mainly because of rapidly increased leukocytes above 10 000/ml. Apart from hyperleukocytosis, side-effects were usually moderate. The comparison of these results with those obtained in a previous trial—in which chemotherapy alone was utilized to treat newly diagnosed APL—revealed significant differences for disease-free and eventfree survival (P ¼ 0:02 and P ¼ 0:006, respectively), but not for CR rate ðP ¼ 0:08Þ; suggesting that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, more importantly, by reducing the relapse rate. Investigators in Japan treated 64 evaluable APL patients with 45 mg/m2/day ATRA in two multi-institutional prospective studies.15 In contrast to the previous French study, only seven of these patients were newly diagnosed, while the remaining 57 were: refractory to initial induction ðn ¼ 21Þ or salvage ðn ¼ 10Þ chemotherapy or in first ðn ¼ 17Þ; second ðn ¼ 5Þ and third ðn ¼ 4Þ relapse, respectively. Despite that, 84% of patients obtained CR and received standard consolidation and maintenance chemotherapy. Toxicity attributable to ATRA was minimal, and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage and elevated serum triglyceridaemia. To reduce the incidence of toxic effects related to ATRA, Castaigne et al had utilized a reduced dosage of ATRA in 30 APL patients, of whom 12 were newly diagnosed.16 The ATRA dose was 25 mg/m2/day until CR; 24/30 patients (80%) achieved CR, three failed, and three died before day 30. However, despite this reduced dosage, there were no differences in terms of therapeutic efficacy, triggering of hyperleukocytosis, or severe toxicity and pharmacokinetic results with ATRA at 25 or 45 mg/m2/day. In 1995 the Japan Adult Leukaemia Study Group published a multi-centre trial comparing ATRA for newly diagnosed APL with a previous Japanese study in which APL patients were treated with standard intensive chemotherapy.17 Of the 110 patients who were entered into the study only 28 (25%) received ATRA alone; of these, 25 (89%) achieved CR. Of the remaining 82 patients, one died before the initiation of treatment and 72/81 (89%) achieved CR, so that the overall CR rate was 89%. Compared to the previous study in which APL patients were treated only with chemotherapy, there was a highly significant difference in remission rate ðP ¼ 0:004Þ; EFS ðP ¼ 0:0007Þ; and also early mortality rate ðP ¼ 0:02Þ: As for toxicity, only 7/110 (6.3%) developed RAS, with one death. Other toxicity associated with ATRA included cheilitis, desquamation, muscle pain and hypertriglyceridaemia. The results of the previous studies demonstrated that ATRA, with or without chemotherapy, leads to an improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL. However, many of the patients who had achieved CR in these studies had also required the addition of standard chemotherapy. Therefore, to avoid the risk that APL patients, depending on the number of white blood cells or blasts, received a different type of treatment, the Italian co-operative group GIMEMA began, in March 1993, a pilot study named AIDA combining ATRA with idarubicin (IDA) for treating newly diagnosed APL patients.18
424 G. Avvisati and M. S. Tallman
ATRA was administered orally beginning on the first day of induction at a dosage of 45 mg/m2/day until complete remission (CR), whereas IDA was administered intravenously at a dosage of 12 mg/m2/day on days 2, 4, 6 and 8 of the induction. Patients who achieved CR were consolidated with three courses of chemotherapy without ATRA. They were then followed up for molecular and haematological CR. Of the 20 consecutive, newly diagnosed patients among 13 participating institutions, four (two with M3v) had leukocyte counts . 10 000/ml. Sixteen patients (80%) were tested for the presence of the PML – RARa hybrid gene at diagnosis by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were found to be RT-PCRþ for the hybrid gene. In the remaining four patients, the cytogenetic study showed the presence of the t(15;17) translocation. CR was achieved by 18/20 (90%) patients after a median time of 36 days; the remaining two patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive haemoptysis, respectively. RAS was observed in only two (10%) patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered. However, after recovering, one patient achieved CR, whereas the other died at day 34 because of massive haemoptysis. Other side-effects were very limited. Interestingly, during recovery from the third consolidation course, only three of 14 (21.4%) tested patients were RT-PCRþ for the PML – RARa hybrid gene. Of these, two relapsed shortly afterwards, whereas the PML – RARa disappeared in the last patient at successive testing performed 2 months later. The results of this study indicated for the first time that: (1) after three consolidation courses, the majority of patients who achieved CR were RT-PCR-negative for the hybrid gene PML –RARa; (2) the persistence of RT-PCR positivity for the PML – RARa hybrid gene after 3 consolidation courses was indicative of early relapse, thus suggesting that these patients still required additional treatment. Summarizing the results obtained in these phase II studies, it was evident that the introduction of ATRA in the treatment of this peculiar subtype of acute myeloid leukaemia had improved its outcome rather in terms of CR rate than in terms of EFS. As a consequence, many investigators initiated phase III or randomized studies to define more accurately the role of ATRA in APL as well as the best way to combine ATRA with standard chemotherapy.
PHASE III STUDIES OF ATRA IN APL With the exclusion of the AIDA pilot study, in which ATRA was combined to IDA alone during induction, all the other phase II studies have utilized as chemotherapy a combination of DNR þ Ara-C. However, even in the AIDA protocol, consolidation courses contained Ara-C. Therefore, to determine the effect of omission of Ara-C from the entire treatment of newly diagnosed APL, Estey and colleagues19, conducted a study in which induction consisted of ATRA (45 mg/m2/day until CR) and IDA 12 mg/m2/day for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2/day for 3 days and then, for 2 years after CR, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2/day for 2 days. The results obtained were compared with those obtained in a historic group of newly diagnosed APL patients given Ara-C with either doxorubicin, amsacrine (AMSA) or daunorubicin without ATRA. The CR rate in the ATRA þ IDA group was 77% and was not
ATRA in APL 425
significantly different from the historic rate. In contrast, a superior overall DFS for the ATRA þ IDA group was registered ðP ¼ 0:03Þ:19 A propsective study omitting Ara-C and utilizing a modified AIDA protocol was published 2 years later by the Spanish co-operative group PETHEMA.20 Newly diagnosed PML –RARa-positive APL were treated with the original AIDA regimen, except for the omission of cytarabine and etoposide from consolidation. Maintenance therapy consisted of 90 mg/m2/day mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and, intermittently, 45 mg/m2/day ATRA for 15 days every 3 months. Of the 123 patients enrolled with newly diagnosed PML –RARa-positive APL, 109 achieved CR (89%), 12 died of early complications, and the remaining two were resistant. Consolidation treatment was associated with very low toxicity and no deaths in remission were recorded. Molecular assessment of response by RT-PCR showed conversion to PCR-negative in 48 of 99 (51%) and 82 of 88 patients (93%) after induction and consolidation, respectively. The 2-year overall survival and EFS were 82 and 79%, respectively. For patients who achieved CR, the 2-year disease-free survival (DFS) was 92%. These data indicated that the omission of Ara-C and etoposide from the original AIDA protocol did not apparently compromise the anti-leukaemic effect, suggesting a minor role for these two drugs in the treatment of newly diagnosed PML – RARa-positive APL patients. An indirect and partial confirmation of both of these results, suggesting that Ara-C can be easily eliminated from the APL treatment protocols, was recently derived from the randomized GIMEMA trial conducted in the pre-ATRA era comparing IDA þ AraC with IDA alone during induction. The results of this study have clearly indicated that IDA monochemotherapy during induction favourably influences the duration of EFS in patients with newly diagnosed hypergranular APL.21
RANDOMIZED STUDIES The first randomized study comparing standard chemotherapy (DNR þ Ara-C) with ATRA followed by the same chemotherapeutic protocol (ATRA group) was the APL 91. Early termination of this trial occurred after the first interim analysis, as EFS was significantly higher in the ATRA group, even though the difference in CR rate between the two groups was not significant.22 As a consequence, the authors suggested that ATRA should be incorporated in the frontline therapy of newly diagnosed APL. The long-term follow-up of this study confirms the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL. In particular, EFS and relapse rate at 4 years were 63 and 31% in the ATRA group, as compared to 17 and 78% in the chemotherapy group (P ¼ 0:0001 and relative risk 2.95, P ¼ 0:0001 and relative risk 3.68, respectively).23 However, despite these results, it was not yet demonstrated whether induction therapy with ATRA alone was superior to chemotherapy alone in newly diagnosed APL. This question was addressed in the randomized study of the North American Intergroup.24 In this study, 346 patients with previously untreated APL were randomly assigned to receive ATRA or DNR þ Ara-C as induction treatment. Patients who had a CR received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy followed by high-dose Ara-C þ DNR. Those patients still in CR after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with ATRA or to observation. CR was obtained by 69% of the patients who had been treated with chemotherapy as compared to 72% of those
426 G. Avvisati and M. S. Tallman
receiving ATRA alone ðP ¼ 0:56Þ: ATRA as induction or maintenance treatment significantly improved disease-free and overall survival as compared with chemotherapy alone. The updated results of this study confirmed that ATRA as induction or maintenance treatment significantly improved disease-free and overall survival as compared with chemotherapy alone. In particular, the 5-year DFS was 16% for patients randomized to DNR þ Ara-C followed by observation, 47% for DNR þ Ara-C followed by ATRA maintenance, 55% for those randomized to ATRA as induction followed by observation, and 74% for the patients randomized to ATRA in induction and maintenance (Figure 1).25 A more complex randomized study was published in 1999 by the European APL Group. In this study, 413 newly diagnosed patients were randomized to two induction schedules: ATRA followed by chemotherapy (CT) and ATRA þ CT, with CT added on day 3 of ATRA treatment. Induction treatment was stratified on white blood cell (WBC) count and age. All patients achieving CR received two additional DNR-Ara-C courses (only one in patients 66 –75 years of age) and were then randomized to one of four maintenance regimens. Overall, 92% of the patients achieved CR, 7% had an early death, and only one patient had leukaemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in five cases. Although the CR rate was similar in all 1.0
Probability
0.8
0.6 0.4 0.2 0.0 0
1
2
3
4
5
6
7
8
9
Years Group DA/ATRA DA/Obs ATRA/ATRA ATRA/Obs
0-2 18/50 40/51 11/49 20/54
Time Interval 2-4 4-6 6-8 6/28 0/18 0/8 1/8 0/6 0/2 1/34 0/26 0/9 2/32 1/24 1/12 (no. events/no. at risk)
Figure 1. Kaplan-Meier product-limit estimates of disease-free survival based on both the induction and maintenance randomizations in the long-term outcome of the North American Intergroup protocol. DA/ATRA ¼ DNR þ Ara-C as induction followed by ATRA as maintenance; DA/Obs ¼ DNR þ Ara-C as induction followed by observation; ATRA/ATRA ¼ ATRA as induction followed by ATRA as maintenance; ATRA/Obs ¼ ATRA as induction followed by observation. Reproduced from Tallman MS et al (All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100: 4298– 4302). Copyright American Society of Hematology, used with permission.
ATRA in APL 427
induction treatment groups, relapse at 2 years was estimated at 6% in the ATRA þ CT group, versus 16% in the ATRA followed by CT group (P ¼ 0:04; relative risk ¼ 0.41). Two hundred and eighty-nine patients were randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous lowdose CT (6 mercaptopurine þ methotrexate) for 2 years, or both, using a 2-by-2 factorial design. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT ðP ¼ 0:0002Þ and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA ðP ¼ 0:02Þ: An additive effect of continuous maintenance CT and intermittent ATRA was observed, and only six of the 74 patients who received both maintenance treatments relapsed. Therefore, results of this study indicated that early addition of chemotherapy to ATRA and maintenance therapy combining continuous CT and intermittent ATRA by reducing the incidence of relapse in APL significantly improved survival.26 To determine the optimal timing and duration of ATRA treatment, the Medical Research Council (MRC) randomized patients with morphologically defined APL to receive a 5-day course of ATRA before commencing CT or to receive daily ATRA commencing with CT and continuing until CR.27 Treatment with extended ATRA resulted in a superior remission rate (87 versus 70%, P , 0:001), due to fewer early and induction deaths (12 versus 23%, P ¼ 0:02), and less resistant disease (2 versus 7%, P ¼ 0:03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20 versus 36% at 4 years, P ¼ 0:04) and resulted in superior survival (71 versus 52 at 4 years, P ¼ 0:005). However, presenting white blood cell count (WBC) , 10 000/ml was a key determinant of outcome. In fact, APL patients who presented with WBC , 10 000/ml had substantial benefit from combining ATRA with induction chemotherapy until remission, whereas patients with a higher WBC did not benefit.
THE ROLE OF MAINTENANCE The role of maintenance treatment, with or without ATRA, in APL has been evaluated by the North American Intergroup24,25 and the European APL ‘9326 trials. Both trials have shown that including ATRA-containing maintenance in the treatment programme gives an advantage in terms of DFS24,25 and relapse rate.26 This issue has also been evaluated by the GIMEMA group which adopted the same four randomization arms of the European APL Group (ATRA versus chemotherapy versus ATRA þ chemotherapy versus observation). However, in contrast to the European APL Group, in the GIMEMA study, only those patients who were found to be RT-PCR-negative for the PML –RARa hybrid gene at the end of three consolidation courses were further randomized.28 This study is currently under evaluation and results will be available soon; however, preliminary data do not confirm the results of the European APL group and American Intergroup (Avvisati G., personal data).
RESISTANCE TO ATRA Primary resistance in PML– RARa-positive APL is rare, and CR can be achieved by almost all ATRA-treated APL patients with a genetically confirmed PML– RARa
428 G. Avvisati and M. S. Tallman
chimeric gene. However, once CR was achieved, the continuous use of ATRA alone produced the appearance of resistance to this drug in the totality of patients with subsequent relapse.29 Subsequently, it was demonstrated that secondary acquired ATRA resistance occurs also in patients who relapsed from regimens combining ATRA and chemotherapy, despite limited ATRA exposure. Therefore, it was suggested that an adaptive hypercatabolic response to pharmacological ATRA levels was the principal mechanism of ATRA resistance.30,31 However, considering that the intermittent administration of ATRA32 or of alternative retinoic formulations such as 9-cys retinoic acid33, Am8034 and liposomal ATRA35,36, was able to bypass this hypercatabolic reaction, hypercatabolism was considered only partially responsible for ATRA resistance. Alternatively, it has been hypothesized that the mechanisms responsible for this resistance were APL cellular alterations limiting the access of the drug to the cell nucleus by cytoplasmic sequestration.37 However, this hypothesis has not been confirmed38, and recent studies suggest that molecular disturbances in APL cells have a predominant role—particularly if disease relapse occurs a few months after discontinuing ATRA therapy39,40 (for a review see Ref. 41).
THE PROGNOSTIC FACTORS Although the introduction of ATRA has greatly improved the CR rate, as well as the overall survival of APL patients, by rapidly ameliorating the severe coagulopathy present in APL at diagnosis, there are still patients dying of fatal haemorrhages.42,43 Therefore, in patients with genetically proven APL who receive ATRA associated with anthracycline-containing chemotherapy, risk factors for CR which, by extension, influence the event-free survival (EFS), include older age and elevated white blood cell count.27,44 Other features affecting the early death rate are the presence of purpura and low platelet number at diagnosis.44 As to the duration of remission and the risk of relapse, white blood cell count above 10 000/ml at presentation was the only factor which correlated with increased risk of relapse in all reported series.23,27,44,45 In addition, both the European APL ‘9123 and a combined analysis of the GIMEMA and PETHEMA groups45 indicated that initial platelet number below 50 £ 109/l or 40 £ 109/l, respectively, also negatively affected the risk of relapse. In particular, a platelet number below 40 £ 109/l was an independent variable associated with increased risk of relapse in the combined GIMEMA and PETHEMA study.45 Several biological characteristics have been analysed for their effect on prognosis. Two recent studies indicated that CD56 may be associated with inferior outcome.46,47 Regarding secondary cytogenetic abnormalities, these do not seem to confer inferior outcome.48 A trend towards inferior outcome was also suggested for patients with the short (or bcr3) PML – RARa isoform as compared to cases with the more frequent long type (or bcr1 – 2). However, except for an early study in patients treated with ATRA alone49, the association of the bcr3 isoform with poorer outcome was not statistically significant in all recent ATRA þ chemotherapy trials.6,27,45,50,51 Slow kinetics of molecular remission, and persistence or conversion to PCR-positive for the PML – RARa after consolidation, has been correlated with increased risk of haematological relapse.27 Finally, internal tandem duplications in the FLT3 gene appear to be associated with an unfavourable prognosis.52
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EXTRAMEDULLARY DISEASE Recent studies and anecdotal reports have suggested that, among patients treated with ATRA, there may be an increased incidence of extramedullary disease, particularly in the central nervous system.53 – 57 It is possible that ATRA perturbs adhesion molecules predisposing to extramedullary disease. Alternatively, the omission of high-dose Ara-C from contemporary therapeutic strategies may play a role.
CONCLUSIONS The data obtained from large co-operative groups indicate that the combination of ATRA and chemotherapy during induction phase results in a CR rate of more than 90%. Moreover, it is worth noting that, when a molecular diagnosis of APL is provided, resistance is rarely observed, suggesting at least an additive effect of ATRA and chemotherapy in treating APL patients. The analyses of the European APL group trial and of the MRC trial confirm that induction treatment combining ATRA and chemotherapy can consistently yield CR rates . 90% on a large multi-centre basis, and suggest, in terms of relapse, a benefit for chemotherapy given concurrently with ATRA treatment.26,27 Alternatively, if an additive effect exists, one should consider the possibility that reduced chemotherapy regimens could be sufficient to induce CR when combined with ATRA, as recently reported by the Spanish co-operative group PETHEMA. Thus, the association of ATRA and a short course of induction chemotherapy appears to be highly effective in inducing CR and reducing toxicity. Moreover, by reducing the toxicity related to the induction therapy, treatment can be intensified during post-remission. In conclusion, from the studies utilizing ATRA for treating APL: 1. The response to ATRA is dependent on the presence of the hybrid gene PML – RARa. Therefore, a morphological diagnosis of APL must always be confirmed by molecular and/or cytogenetic analysis. 2. A concurrent administration of ATRA and chemotherapy is better than a sequential administration of ATRA after chemotherapy. 3. In contrast to other AMLs, the induction treatment of APL using ATRA-based protocols does not seem to require the use of Ara-C, when an adequate dose of anthracycline is administered. Data suggest that Ara-C may also be omitted from consolidation, although long-term results of these trials are required to clarify this issue. 4. Once CR is achieved, patients must be consolidated with at least two cycles of standard consolidation regimens.
Practice points † all-trans retinoic acid (ATRA) should be incorporated in the treatment of all patients with APL † the retinoic acid syndrome (RAS) constitutes the most important and lifethreatening complication of ATRA therapy
430 G. Avvisati and M. S. Tallman
† early recognition of RAS and institution of dexamethasone, is mandatory and usually results in complete resolution of the syndrome † the concurrent administration of ATRA and chemotherapy for induction appears to decrease the relapse compared to ATRA for induction † maintenance therapy with ATRA, with or without low-dose chemotherapy, is beneficial † the achievement of a molecular negative status, RT-PCR for the PML –RARa fusion transcript, is the desired therapeutic endpoint
Research agenda † decrease the early mortality rate resulting from haemorrhage † identify ways of preventing the retinoic acid syndrome † continue to identify patients at particularly low or high risk of relapse in order to tailor therapy † complete long-term randomized study (currently ongoing) to determine whether Ara-C can be excluded from induction and/or consolidation
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